Personalized nutritional strategies to treat obesity may specifically influence inflammatory markers, in addition to reduce body weight. In the present study, we evaluated the effect of a hypocaloric diet based on a Mediterranean dietary pattern (MDP) on nutritional status as well as on plasma concentrations of retinol binding protein-4 (RBP4) and other proinflammatory markers. Fourty-one subjects (24F/17M; age: 37 ± 7 years; BMI: 32.2 ± 3.9 kg/m²) were assigned to follow a MDP within a caloric-restricted diet over an 8-week period. Anthropometrical, clinical, and biochemical variables were measured at baseline and endpoint after the nutritional program. Dietary intervention resulted in a mean weight loss of -4.4 ± 2.5 kg (P < 0.001) and marked reductions (P < 0.05) in plasma concentrations of RBP4, leptin, C-reactive protein, complement C3, and tumor necrosis factor-alpha (TNFα). Individuals with a higher adherence to the MDP during the nutritional intervention presented differentially higher reductions (P < 0.05) in plasma RBP4, IL6, and TNFα. In addition, the increase in the Mediterranean diet score from baseline was a significant and independent predictor factor for the decrease in plasma RBP4 concentration (P < 0.05). In conclusion, our findings suggest that following a hypocaloric diet accompanying a high adherence to a MDP resulted in specific reductions on proinflammatory markers, in addition to a significant improvement in some metabolic syndrome features induced by weight loss, which could be a good combined strategy to treat obesity as well as related metabolic and inflammatory disorders.